In Silico Prediction of Binding Affinities of Hybrid Molecules of Benzothiazole Linked with Hydroxamic Acid by Disulfide Bond and Certain Linkers with HDAC8 Enzyme

Abstract

A new hybrid molecule of Benzothiazole cross-linked with hydroxamic acid through an amino acid or aminoalkanoic acid were synthesised. All the synthesized hybrid molecules (1-5) were subjected to molecular docking studies to evaluate their binding affinities with histone deacetylase enzyme (HDAC8, PDB ID: 1T69) and recorded lower ΔG (-8.276, -10.093, -8.647, -6.315, -8.676 kcal/mole, respectively) than the reference ligand (Vorinostat, suberoylanilide hydroxamic acid, SAHA -5.375 kcal/mole). Molecular docking studies were performed using the maestro software (Schrödinger, version 2022-1). Moreover, compound 2, which is Benzothiazole-p-amino benzoic acid-hydroxamate has recorded the lowest binding score (-10.093). This may indicate that this compound is the most potent hybrid molecule. There were no violations from Lipinski’s rule and all the synthesized hybrid molecules comply with all parameters. Swiss ADME server was employed for the in silico molecular docking for prediction of the physicochemical and ADME properties of the investigated compounds. All hybrid molecules showed low possible passive oral absorption and no penetration into BBB. The hybrid molecules 1and 3 may be considered as P-gp substrates.

Keywords

• Benzothiazole
• Amino acids
• Molecular hybridization
• Vorinostat
• HDACs inhibitors